Novel pyrazolidin-3, 5-diones



United States Patent 3,133,?34 NOVEL PYRAZOLIDHW-Sfi-DIONES Donald P. Cameron, New London, Conn, assignor to Chas. Pfizer & Co., Inc, Brooklyn, N.Y., a corporation of Delaware No Drawing. Filed Sept. 1, 1961, Ser. No. 135,421 7 Claims. (Cl. 260-310) wherein R and R are each selected from the group consisting of aryl, heteroaryl, \alicyclic, hetero-interruptedalicyclic, lower alkyl, lower alkoxy carbonyl, carbamyl, lower alkyl carboxamido and phenyl oarbamyl; R and R are each selected from the group consisting of alkyl, phenyl, substituted phenyl, heteroaryl and, when taken together with the germinal carbon atom, cycloalkyl and heterodnter-rupted-alkyl.

A preferred class of compounds are those of the above structural formula wherein R and R are selected from the group consisting of phenyl, halophenyl, hydroxyphenyl, lower alkoxy phenyl, lower carboalkoxy phenyl, said lower alkoxy radicals having up to 3 carbon atoms, lower alkyl meroapto phenyl, alkyl phenyl, said alkyl radicals having up to 5 carbon atoms, trifluoromethyl phenyl, pynidyl, thienyl, thiazolyl; R and R are each selected from the group consisting of lower alkyl, phenyl, lower alkoxy phenyl, said lower alkoxy radicals having up to 3 carbon atoms, lower [alkyl mercapto phenyl, alkyl phenyl, said alkyl radicals having up to 5 carbon atoms, trifluoromet-hyl, pyridyl, thienyl, thiazolyl, and when taken together with the geminal carbon atom, cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl and lower alkyl substituted cycloal kyls of this type as Well as piperidyl and N alkyl piperidyl.

A particularly valuable group are those compounds of the generic formula and the pharmaceutically acceptable salts thereof, wherein R is selected from the group consisting of phenyl and panahydroxyphenyl,

R when taken separately is selected from the group consisting of alkyl of up to four carbon atoms, pyridyl, thienyl, thiazolyl, phenyl and mono-substituted phenyl wherein said substituent is selected from the group consisting of hydroxy, alk'oxy of up to three carbon atoms and alkyl and alkyl meroapto of up to five carbon atoms,

R when taken separately is selected from the group consisting of methyl and ethyl, provided that R is methyl when R is alkyl, and

-R and R when taken together with the quaternary carbon atom to which they are attached from a cyclic substituent selected from the group consisting of cyclobutyl, cyclopentyl, monoalkyl cyclopentyl, cyclohexyl, monoalkyl cyclohexyl, cycloheptyl, piperidyl and N-alkyl piperidyl, each of said alkyl substituents having up to two carbon atoms.

The compounds of the present invention may be formed, according to the general reaction illustrated by the following chemical equations:

In the first step of the above reaction, the appropriately substituted pyrazolidin-3,5-dione is contacted with a ketone.

Although the ratio of the reactants is not critical, it has been found that the use of at least equimolecular quantities of ketone will give good yields and an excess is to be preferred. In fact, a considerable excess of ketone may be employed as a solvent.

The time and temperature for this reaction will vary somewhat depending upon the nature of the reactants. However, the desired alkylidene compound is formed if the reaction is carried out at a temperature from about 50 to about C. for a period of about 1 hour to about 10 hours. Steric factors are important considerations in determining the speed of the reaction. For instance, acetone will react more quickly than acetophenone and the latter will react more rapidly than benzophenone.

As previously noted, the reaction may be carried out in the presence of excess ketone as a solvent. Other solvents for the reaction are organic acids having up to 5 carbon atoms such as acetic acid; also, hydrocarbons or halogenated hydrocarbons having up to 7 carbon atoms may be employed. The hydrocarbon and halogenated hydrocarbon solvents may contain up to 10% organic acid by volume.

In some cases, the final product will precipitate with cooling. In most cases it will precipitate when the reaction mixture is poured into water. If the product does not precipitate upon cooling, a small portion of the reaction mixture can be poured into water in order to determine whether a precipitate will form under those conditions. If a precipitate is not obtained under either of the preceding conditions, or if one wishes to avoid the time needed for cooling, the reaction mixture can be dried by removing the solvent in vacuo, for instance at a pressure of l to 20 mm. Hg. The residue is purified by washing the 'dilute aqueous Na CO and then with water. The purified product is recrystallized from a suitable solvent such as a lower alkanol, for instance, methyl or ethyl alcohol, or from ethyl acetate.

While a catalyst is not essential in the preceding reaction, a small amount of a proton acceptor, such as ammonium acetate, sodium methoxide, pyridine, etc., facilitates the reaction.

The water formed during the reaction may be removed by using a suitable water trap or by the use of an equivalent amount of acetic anhydride. However, the reaction will proceed satisfiactorily even though the water is not removed.

In the second step of the reaction, i.e., the conversion of the alkylidene compound to the nitrile compound, an

aqueous solution containing the cyanide anion or hydrogen cyanide (as a solution or gas) is added to the alkylidene compound at a temperature from about 80 C. to about 100 C. It is convenient to use to W./v. solutions of an alkali metal cyanide such as sodium cyanide. If at least equimolecular quantities of the cyanide ion or hydrogen cyanide, are used, it is possible to obtain a good result. In order to facilitate the reaction, the medium is usually stirred as the aqueous cyanide or hydrogen cyanide is added.

The reaction provides two concurrent end points; first, the nitrile compound is soluble whereas the alkylidene compound is insoluble; secondly, the alkylidene compound is colored whereas the nitrile solution is not. Excess cyanide ion or hydrogen cyanide is not harmful and may help assure maximum yield.

The nitrile compound may also be obtained by dissolving the alkylidene compound in a water-miscible solvent like dioxane, dimethylformamide or a lower alkanol, preferably t-butanol. The aqueous cyanide solution or hydrogen cyanide is then added as above.

Other modifications of the two procedures will be obvious to those skilled in the art. For instance, it is unnecessary to purify the residue of the first step before adding the cyanide.

The reaction medium is acidified with an aqueous solution of mineral acid, such as HCl, until a pH of about 2 to 3 is obtained. At this point, the desired product precipitates from solution. The completeness of the precipitation can be tested by adding more water. The precipitated product is then dissolved in a solvent such as a lower alkanol or ether, acetone or ethyl acetate, and the desired product is recrystallized therefrom.

The compounds of the present invention are valuable non-steroidal antiinflamatory agents. They compare favorably with phenylbutazone in this respect. For instance, administration of these compounds reduces the area of irritation produced by foreign bodies implanted in rats. When administered orally they also inhibit writhing in mice and control yeast-induced edema in rats. These are standard tests for analgesic and/ or anti-inflammatory activity. 1,2-diphenyl-4-(1'-cyano)cyclohexylpyrazolidin-3,5-dione is particularly effective in these tests.

In certain cases, it may be found that absorption of the compound into the system is poor due to low solubility in water. Since the new compounds are acidic, absorption may usually be increased by administering them in the form of pharmaceutically acceptable salts, i.e. those formed by reaction with inorganic or organic bases which do not substantially increase the toxicity of the active agents.

Suitable bases for the preparation of pharmaceutically acceptable salts include the hydroxides, carbonates and bicarbonates of the alkali metals, sodium and potassium, and of alkaline earth metals of atomic number up to and including 20, i.e. magnesium and calcium, as well as ammonium, aluminum, zinc, iron and manganese, among others; and additionally organic bases of adequate strength such as dibenzylethylenediamine and such water-soluble amrnes as the lower alkanolamines, including ethanolamine and the like.

Of course, the pharmaceutically unacceptable salts, while not suitable for therapy, are useful for isolation and purification of the new compounds, as well as for preparat1on of the pharmaceutically acceptable salts. Pharmaceutically unacceptable salts include most commonly salts of lithium and of alkaline earth metals of atomic number greater than 20, i.e. barium and strontium.

The salts may be prepared by treating the new products of the present invention in solution with an equimolar proportion, or a slight excess, of the chosen base. In the case of the water-soluble bases, the active agents may be treated in a water-miscible solvent such as dimethoxyethane with a water solution of the base. The more insoluble salts precipitate immediately and may be recovered by filtration, while others will crystallize upon partial evaporation of the solvent, or addition of a nonsolvent. The most soluble salts may be recovered by evaporation to dryness followed by washing of the residue with a non-solvent such as alcohol.

The following examples illustrate the present invention and are not to be construed as limitations thereof. It is apparent from the preceding description and the appended claims that many variations of the examples are possible without departing from the spirit or scope of the invention.

EXAMPLE 1 1,2-Diplzenyl-4- (1 'M ethyl-1 -Cyan0)Ethylpyraz0lidin-3,5-

Dione Ten ml. of acetone (approximately 7.9 grams) are added to 0.1 mol of 1,2-diphenyl-pyrazolidin-3,S-dione. The mixture is stirred and then heated to 50 C. for 2 hours. The desired alkylidene intermediate is obtained by distilling off the solvent in vacuo. The dried residue is washed with 100 ml. of 2% Na CO and then with two 100 ml. portions of water. The resultant product is recrystallized from ethyl alcohol.

In a modification of the preceding reaction, the dione compound is added directly to 200 ml. of acetone. The acetone thus is used both as a reactant and as a solvent. By employing the same reaction conditions set forth above, substantially identical results are obtained.

To 0.05 mol of the alkylidene product of the preceding sections, a 10% aqueous solution of sodium cyanide is slowly added at room temperature with stirring until the characteristic color of the alkylidene compound is no longer discernible.

The reaction mixture is extracted with an equal volume of chloroform. After this extraction step has been repeated twice more, the aqueous layer is acidified with 1.0 N HCl. A precipitate appears when the pH has been adjusted to approximately pH 3. The precipitate is separated by filtration and then recrystallized from isopropyl alcohol to obtain the desired l,2-diphenyl-4-(1'- methyl-1-cyano)ethyl-pyrazolidin-3,5-dionez I CN melting point 176177 C.

EXAMPLE 2 1,2-Dfplzcnyl-4-(1 'Cyalzo) Cyclohexyl-Pyraz0lidin-3,5- Dione 0.1 mol of l,Z-diphenyl-pyrazolidin-3,5-dione is mixed with 200 ml. of cyclohexanone in the presence of 20 ml. of pyridine. The mixture is heated on a steam bath for 10 hours, after which the solvent is evaporated in vacuo.

The residue is then washed with three ml. portions of water and the residue is recrystallized from methyl alcohol.

0.05 mol of the preceding alkylidene intermediate is dissolved in sutlicient dimethyl formamide to effect com plete solution. 5% aqueous potassium cyanide is then added dropwise at 0 C. until the color of the alkylidene compound is no longer observed. The reaction mixture is then extracted three times with an equal volume of ether each time.

The aqueous layer is acidified until a precipitate forms. The completeness of the precipitation is tested by adding. 10 cc. more water. No additional precipitate forms, in-- dicating that precipitation is complete.

The product is recovered by filtration and recrystallized,

5 from acetone. It melts at 180-181 C. and has the following structural formula:

Elemental analysis-Calculated: C, 73.51%; H, 5.89; N, 11.69. Found: C, 73.59; H, 5.68; N,.11.57. Ultraviolet absorption maxima are observed at 239 mp. (E %=411) in 0.01 N HCl, methanol, and at 262 mp (E 633) in NaOH.

When the described reaction is repeated substituting 4-methyl cyclohexanone for cyclohexanone, the product obtained is 1,2-diphenyl-4-( 1'-cyano-4'-rnethyl) cyclohexyl-pyrazolidin-3,S-dione, melting at l78179 C.

Elemental analysis.-Calculated: C, 73.97%; H, 6.21; N, 11.25. Found: C, 74.31; H, 6.15; N, 11.15. An ultraviolet absorption maximum is observed in 0.01 N HCl at 239 m (E %=428). When the experiment is repeated with addition of the cyanide at 80 C., 1,2-diphenyl 4 (1 cyano-4'-methyl)cyclohexyl-pyrazolidin- 3,5-dione melting at 187.5-1885" C. is obtained. The difference in melting point is attributed to stereoisomerism. Both products are found to be therapeutically active.

EXAMPLE 3 1,2-Diphenyl-4-(1-Cyano-1 -Ethyl)Ethyl-Pyrazolidin- 3,5-Dirte 0.5 mol 1,2-diphenyl-pyrazolidin-3,S-dione is dissolved in acetic acid, and 100 cc. of methyl ethyl ketone is stirred into the solution. Two grams sodium acetate is then added to the solution after which the mixture is heated to 120 C. for 4 hours. The reaction mixture is allowed to cool to room temperature and is then poured into an equal volume of water. The desired alkylidene intermediate precipitates and is separated by filtration. After washing with 3 x 50 ml. of 5% Na CO it is recrystallized from isopropyl alcohol.

0.1 mol KCN in saturated aqueous solution is added to 0.1 mol of the alkylidene product obtained in the process of the preceding paragraph. The addition is carried out at 20 C. After all the KCN has been added, the solution is washed with an equal volume of ether. The aqueous solution is next acidified with H 80 to pH 2. The resulting precipitate is separated by decanting off the bulk of the liquid and passing the remainder through a filter. After recrystallization from isopropanol the product, melting at 150-152 C., is obtained.

EXAMPLE 4 1,2-Diphenyl-4- (1-Cyan0-1'-Is0pr0pyl) Elhyl-Pyrazolidin- 3,5-Di0ne A solution of 0.2 mole 1,2-diphenyl-pyrazolidin-3,5- dione in 500 ml. methyl isopropyl ketone is heated to 75 C. for 8 hours. The resultant solution on cooling yields a precipitate of 1,2-diphenyl-4-(3'-methyl-butylidene-2 -pyrazolidin-3 ,S-dione.

Aqueous NaCN solution is added to the mixture until the precipitate is dissolved. The mixture is extracted twice with 150 ml. methylene dichloride, after which the aqueous phase is acidified with 1 N HCl until a precipitate is formed. The precipitate is separated and recrystallized from isopropanol. It has the following structural formula:

When methyl n-propyl ketone is substituted for methyl isopropyl ketone in the above-described preparation the corresponding (l-cyano-l'-n-propyl) ethyl compound is obtained.

EXAMPLE 5 1,2-Diplzenyl-4- (1 -Cyan0) Cyclopentyl-Pyrazolidin- 3,5-Di0ne 0.1 mol of 1,2-diphenyl-pyrazolidin-3,5-dione is dissolved in excess cyclopentanone. After 5 grams of ammonium acetate have been added, the mixture is heated for 10 hours at C.; then the excess solvent is distilled at 20 mm. Hg. The residue is washed successively with 200 ml. 5% Na CO and 200 ml. H O. It is recrystallized from methyl alcohol.

Concentrated aqueous NaCN is slowly added to the residue with stirring at 0 C. until the color of the alkylidene compound is lost. The resultant solution is extracted with 2 x ml. ether. The aqueous layer is adjusted to pH 2 with 10% HCl, and the resultant precipitate is separated by filtration. The filtered product is recrystallized from methanol. Melting point 174- 175 C.

When 3-rnethyl cyclopentanone is substituted for cyclo pentanone in the described procedure, the corresponding (1-cyano-3'-methyl)cyclopentyl product is obtained. The latter melts at 130131 C. and exhibits the following elemental analysis. Calculated: C, 73.51%; H, 5.89; N, 11.69. Found: C, 73.65; H, 5.71; N, 11.68.

EXAMPLE 6 23.15 g. of p-hydroxy acetophenone and 25.2 g. of 1,2- diphenyl-pyrazolidin-3,S-dione are dissolved in 90 ml. of acetic acid, 0.8 g. of ammonium acetate is added and the mixture is heated for one hour under nitrogen on a steam bath. The mixture is cooled to room temperature and, after standing several hours, the product is filtered, washed with acetic acid containing 10% water and dried in air. It weighs 10.1 g. and melts at 197-210 C. with decomposition. The mother liquor is concentrated to an oil and is crystallized from ZB-ethanol to obtain 16.4 g. of the desired intermediate melting at 197209 C. with decomposition.

The intermediate obtained as described above (18.5 g.) is dissolved in 200 ml. of dioxane. To this solution is added, at a temperature of 0 to 5 C., a solution of 9.8 g. of sodium cyanide in 250 ml. of water. The mixture is allowed to warm to room temperature and is maintained at this temperature overnight. An additional 2.5 g. of sodium cyanide is then added and the mixture is stirred for 2 hours. The resulting white precipitate is filtered. The filtrate is cooled and a mixture of equal volumes of concentrated hydrochloric acid and water (40 ml.) is added drop by drop until a pH of 6 7 is reached. Addition of a further 0.5 ml. now brings the pH to 2. A white oily precipitate forms which is extracted with methylene dichloride. The solvent extract is dried over anhydrous magnesium sulfate and the solution is allowed to stand at room temperature. The solution is then filtered, and the solvent is removed under vacuum to obtain 28.8 g. of a glass. This product is crystallized from a mixture of methanol and methylene dichloride. After a recrystallization from the same solvent mixture, it melts at 223 225 C. with decomposition.

EXAMPLE -7 1- (p-Hydroxyphenyl).-2-Phenyl-4-(1 '-Cyan0) -Cycl0hexyl- Pyrazolidin-iS-Dione 15.5 grams of 1-(p-acetoxyphenyl)-2-phenylpyrazolidin- 3,5-dione and 7.0 g. of cyclohexanone in 50 ml. of acetic acid containing 0.4 g. of ammonium acetate and 2.0 g. of acetic anhydride are heated for 3 /2 hours under nitrogen at a temperature of 100-115 C. The mixture is then permitted to stand at room temperature for 12 hours. The acetic acid is distilled off under vacuum and the residue is crystallized from ZB-ethanol. The intermediate weighs 15.65 g. and has a melting point of 131133 C. After several recrystallizations, it melts at 131-133 C. and exhibits the following analysis:

Percent Carbon 70.75 Hydrogen 5.68 Nitrogen 7.8

15.0 grams of the condensation product of l-(p-acetoxyphenyl)-2-phenylpyrazolidin-3,S-dione and cyclohexanone is now dissolved in 100 ml. of dioxane, This solution is added dropwise to a solution of 5.64 g. of sodium cyanide in 75 ml. of water at to C. The mixture is stirred under nitrogen. During addition, a light yellow precipitate forms. After stirring an hour and a half, the solution becomes clear. It is permitted to stand at room temperature for 16 hours, and 100 ml. of Water is added. The solution is extracted with methylene dichloride using 4 ml. portions. The aqueous solution is now acidified at a temperature of 0 to 5 C., using 35 ml. of hydrochloric acid and adjusting the mixture to a pH of 2. After stirring for one hour under nitrogen, the mixture is filtered. The product is washed with water and the light pink solid is dried at room temperature. It weighs 14.15 g. and has a melting point of 183187 C. After recrystallization from isopropanol and methylene chloride, it melts at 185- 187 C. During the process, the acetoxy group has been hydrolyzed. Thus, the product is 1- (p-hydroxyphenyl)-2- phenyl-4-( 1'-cyano) -cyclohexylpyrazolidin-3,5-dione.

EXAMPLE 8 Following the procedure of the preceding examples, the products tabulated below are prepared from the appropriate ketones:

o 0oH5N- i H R ci3 R' CoNs-N-fi (1N R R Phenyl Methyl. o-Hydroxyphenyl Do. o-Methoxyphenyl Ethyl.

--CH CH N( CH CH CH p-Methylphenyl Methyl. Pyridyl Ethyl.

CH CH CH CH CH CH CH CH CH CH CH(CH )CH CH CH n-Butyl Methyl. i-Butyl Do. 2'-Thienyl Do. 5-Thiazolyl Do. m-Propylphenyl Do. p-Amylphenyl Do, p-Methylmercaptophenyl Ethyl. m-Butylmercaptophenyl Methyl. p-Propoxyphenyl CH CH CH(C H )CH CH CH CH CH(C H )CH CH -CH CH NHCH CH CH N (C H CH CH CH s-Butyl Methyl.

EXAMPLE 9 Following the procedure of Example 7, the products tabulated below are prepared from 1-(p-acetoxyphenyl)- 8 2-phenylpyrazolidin-3,S-dione and the appropriate ketones:

Methyl Methyl. Ethyl Do. n-Butyl Do.

CH CH (CH CH CH -CH CH CH CH CH CH V Phenyl Ethyl.- p-Hydroxyphenyl Do. p-Methoxypheuyl Methyl. 2'-Thiazolyl Do. Pyridyl Do. Isopropyl D0. 3 -Thienyl Ethyl. p-Methylphenyl Do.

EXAMPLE 10 The sodium salt of 1,2-diphenyl-4-(1'-cyano)cyclohexyl-pyrazolidin-3,5-dione is prepared by treating a solution of the product of Example 2 in dimethoxyethane with an equivalent proportion of aqueous sodium hydroxide and evaporating. In similar fashion other salts, including the potassium, calcium, magnesium, lithium, strontium, ammonium and ethanolammonium salts are prepared from the products of the previous examples. In the case of the most soluble salts the reaction mixture is lyophilized and the residue purified by Washing with a little cold alcohol. The less soluble salts are recovered by filtration, preceded by partial evaporation Where required.

What is claimed is:

1. A compound selected from the group consisting of those of the formula:

R-N- I and the pharmaceutically acceptable salts thereof wherein R is selected from the group consisting of phenyl and parahydroxy phenyl; and wherein n is an integer of from 3 to 6.

3. 1,2-dipheny1 4 (1' cyano)cyclohexyl pyrazolidin-3,5-dione.

4. 1,2 diphenyl 4 (1' cyan0)cyclopentyl pyrazolidin-3,5-dione.

5. A compound selected from the group consisting of those of the formula:

H C J R1 phenyl-N-fi] lN and the pharmaceutically acceptable salts thereof wherein R is selected from the group consisting of phenyl and parahydroxyphenyl; R and R together with the quaternary carbon to which they are attached form a cycloalkyl substituent selected from the group consisting of monoalkyl cyclopentyl and monoalkyl cyclohexyl, each having up to two carbon atoms in the alkyl substituent.

6. 1,2 diphenyl 4 (1' cyano 3 methy1)cycl0- pentyl-pyrazolidin-3,S-dione.

7. 1,2 diphenyl 4 (1' cyano 4' methyl)cycloheXyl-pyrazolidin-3,5-dione.

References Cited in the file of this patent Chemical Abstracts, vol. 14-40, 1920-46, Collective Formula Index, p. 115.

Logemann et al.: Chemische Berichte, vol. 88, pp. 1353-1360 (1955). 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE OF THE FORMULA:
 2. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE OF THE FORMULA: 